Cassette apparatus utilizing electric energy for processing of blood to neutralize pathogen cells therein

ABSTRACT

An operational unit for locating and neutralizing pathogen cells in blood. A cassette has a plurality of thin holding chambers that are filled with blood drawn from a patient. A light source illuminates each of the holding chambers and passes light to an underlying sensor array such that the cells in the blood produce shadow images of the cells in the sensor array. A processor performs pattern recognition to identify and locate the pathogen cells by use of an image library. After the pathogen cells are located, the pump is operated to move the identified cells to a processing zone. When each identified cell reaches the processing zone, electric energy is applied to destroy the identified pathogen cells. A pump refills the cassette holding chambers, returns the neutralized-pathogen blood to the patient, and the process is repeated for a treatment time period.

CROSS REFERENCE TO RELATED APPLICATIONS

Applicants have concurrently filed additional applications related tothe subject matter of the present application. These are: Ser. No.17/814,536 filed Jul. 25, 2022; Ser. No. 17/814,537 filed Jul. 25, 2022;Ser. No. 17/814,538 filed Jul. 25, 2022; Ser. No. 17/814,539 filed Jul.25, 2022; Ser. No. 17/814,541 filed Jul. 25, 2022; Ser. No. 17/814,542filed Jul. 25, 2022; Ser. No. 17/814,543 filed Jul. 25, 2022; Ser. No.17/814,545 filed Jul. 25, 2022; Ser. No. 17/814,547 filed Jul. 25, 2022;Ser. No. 17/814,548 filed Jul. 25, 2022, and Ser. No. 17/814,549 filedJul. 25, 2022.

BACKGROUND Field of the Invention

The present invention is in the field of biotechnology, semiconductortechnology and further the medical field of treating individuals whohave an infection of pathogen cells in the bloodstream.

Description of the Related Art

The presence of bacteria in human blood is a serious condition termed“bacteremia”. This condition can cause an infection that spreads throughthe bloodstream. This can also be termed “septicemia” which is definedas the invasion and persistence of pathogenic bacteria in thebloodstream. Such an infection can lead to a condition termed “sepsis”which is the body's reaction to the infection. Sepsis is a seriouscondition that can cause intense sickness including shock, and in somecases, can lead to the death of the infected person. A common pathogenicbacterium causing such infection is E. coli, but infections can also becaused by other pathogenic bacteria and organisms such as the fungusCandida auris. The usual treatment for the patient is the application ofantibiotics to try to kill the pathogenic cells in the bloodstream.However, this treatment is not successful for many patients with abloodstream infection.

BRIEF DESCRIPTION OF THE DRAWINGS

For a more complete understanding of the present invention and theadvantages thereof, reference is now made to the following descriptiontaken in conjunction with the accompanying drawings in which:

FIG. 1 is a perspective view of an overall system which includes anoperational unit and a system control unit,

FIG. 2 is a perspective view showing the interior of the enclosure 11shown in FIG. 1 ,

FIG. 3 is an elevation, section view of components inside theoperational unit shown in FIG. 1 ,

FIG. 4 is a plan view of the compression plate 51 shown in FIG. 3 ,

FIG. 5 is a bottom view of the light source shown in FIG. 3 with anarray of light generators,

FIG. 6 is an elevation, sectional view of a collimated beam lightgenerator, as shown in FIG. 5 ,

FIG. 7 is an elevation section view of the cassette 58 shown in FIG. 3 ,

FIG. 8 is a functional block diagram including additional components forthe system shown in FIG. 1 ,

FIG. 9 is a top-down view illustrating the primary blood flow throughthe cassette 58 shown in FIG. 3

FIG. 10 is a section view along line 10-10 in FIG. 9 ,

FIG. 11 is a section view along line 11-11 in FIG. 9 ,

FIG. 12 is a is a section view along line 10-12 of FIG. 9 ,

FIG. 13 is a partial cutaway view of cassette 58, pump 62 and flow lines22 and 24 shown in FIG. 3 ,

FIG. 14 is a top-down view of the top layer of the cassette 58, shown inFIG. 3 illustrating the flow of blood through the input manifoldchannels, holding chambers and output manifold channels,

FIG. 15 is a view of a cassette 58 holding chamber having a plurality ofparallel ridges therein and multiple zones,

FIG. 16 is a section, perspective view of a portion of the cassettechamber shown in FIG. 15 ,

FIG. 17 is a top view of a portion of the cassette chamber shown in FIG.15 ,

FIG. 18 is a section view of a portion of the cassette chamber shown inFIG. 15 together with a section view of a chamber driver,

FIG. 19 is a bottom view of hemispherical pads mounted on the drivershown in FIG. 18 ,

FIG. 20 is a top view of flat electrical connection pads shown in FIG.18 ,

FIG. 21 is an electrical schematic block diagram of the chamber drivershown in FIG. 18 ,

FIG. 22 is a section perspective view of an alternate configuration tothe structure shown in FIG. 16 at a portion of the cassette chambershown in FIG. 14 ,

FIG. 23 is a top view of an alternate configuration to that shown inFIG. 17 for a portion of the cassette chamber shown in FIG. 14 ,

FIG. 24 is an electrical block diagram of the system shown in FIG. 1 ,

FIG. 25 is a top view of a light sensor array with control and datalines,

FIG. 26 is an electrical schematic of a 3T image sensor cell,

FIG. 27 is an electrical schematic of a 4T image sensor cell,

FIG. 28 is a top view of a layout of an image sensor cell,

FIG. 29 is a section view of a layout of an image sensor cell,

FIG. 30 is an illustration of cassette chamber zones used for physicalcalibration,

FIG. 31 is an illustration of a cassette chamber zone with a calibrationmarker,

FIG. 32 is a planar illustration of a portion of a sensor arrayillustrating physical calibration,

FIGS. 33A and 33B are a flow diagram illustrating a light sourceamplitude calibration process,

FIG. 34 is a set of pathogen image views for pattern recognition,

FIG. 35 is a set of red blood cell images for pattern recognition,

FIG. 36 is a set of white blood cell images for pattern recognition,

FIG. 37 is a set of platelet cell images for pattern recognition,

FIG. 38 is an illustration of blood flow in chamber channels for traveltime calibration,

FIG. 39 is a travel time versus fluid velocity chart for travel timecalibration,

FIGS. 40A, 40B and 40C are a logic flow diagram illustrating a traveltime calibration process,

FIGS. 41A, 41B and 41C are a logic flow diagram illustrating anoperational process to identify pathogen cells and move the identifiedcells to a processing zone in a chamber for neutralization, and

FIG. 42 illustrates electrical waveforms applied to electrodes in thechannels of the processing zone of the chamber for neutralizing pathogencells.

SUMMARY OF THE INVENTION

An embodiment of the present invention comprises an apparatus for firstexamining blood by imaging a first quantity of blood in a chamber toidentify and locate pathogen cells in this quantity of blood. Thepathogen cells thus identified are moved to a processing zone of thechamber and are then neutralized by the application of electric energyin the processing zones. The first quantity of blood, now processed, isthen replaced with multiple subsequent quantities of blood and theprocess of identifying, locating and neutralizing pathogen cells isrepeated for each quantity of blood. After these processing operationsare performed repeatedly over a period of time, the count of viablepathogen cells in the patient blood is decreased.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is an apparatus for identifying pathogen cells inblood and neutralizing the identified cells to reduce the count of suchcells in the blood and thereby potentially reducing the harmful effectof the pathogen cells to a patient.

Referring now to FIG. 1 , there is shown a system for processing bloodwhich identifies and determines locations of individual pathogen cellsin blood and then applies to located pathogen cells electric energy ofsufficient magnitude to neutralize (kill) the identified pathogen cells.The applied energy is limited to a restricted region surrounding theidentified pathogen cell such that nearby blood cells, such aserythrocytes (red blood cells), leukocytes (white blood cells) andplatelets are subjected to little or no electric energy exposure.

The principal operations performed with the blood are carried out in anoperational unit 10 which is connected by a data and control cable 12 toa system controller 14 which can be, for example, a laptop computer orcomputer work station. The operational unit 10 receives electrical powervia a power line 16.

The operational unit 10 is connected to a patient 18 by means of atwo-lumen (two fluid channels) catheter 20. In this example, thecatheter 20 is inserted into an artery in the leg of patient 18 to bothreceive blood from the patient and return blood to the patient. Thecatheter 20 has one lumen thereof connected to a blood input line 22which is connected to operational unit 10 and has a second lumenconnected to a blood return line 24 which is also connected to theoperational unit 10. The blood of patient 18 flows into the catheter 20,through input line 22 to the operational unit 10 and from theoperational unit 10 through the return line 24 and catheter 20 back tothe patient 18. A catheter, such as 20, is described in U.S. Pat. No.6,872,198 issued Mar. 25, 2005 which patent is incorporated herein byreference in its entirety.

Within the operational unit 10 the blood is imaged to identify andlocate pathogenic cells in the blood followed by neutralizing thelocated pathogenic cells at a subsequent location. This processcontinues over a period of time with a flow of blood from the patientwith the goal of reducing the number of pathogenic cells in thepatient's blood.

The operational unit 10 includes an enclosure 11 having a top lid 11 awhich can be opened by use of a handle 11 b which rotates the lid 11 aon hinges 11 c. A thermal control unit 26, for example a heat pump,supplies heated or cooled air at a selected temperature through a duct27 to the interior of the enclosure 11. The thermal control unit 26 isoperated by the system controller 14 via a cable 28. The systemcontroller 14 monitors temperature inside the enclosure 11 and controlsthe thermal control unit 26 to supply air to drive the temperature inthe enclosure 11 to a preselected temperature or temperature range. Theenclosure 11 has an opening 46 for passage therethrough of flow tubesand electrical conductors.

An embodiment of the invention described in the following text andcorresponding drawings utilizes electric energy (applied as field orcurrent) to neutralize located pathogen cells in blood. The electricenergy is of sufficient intensity to kill the pathogen cells which havebeen located in the blood.

The interior of the enclosure 11, shown in FIG. 1 , is illustrated inFIG. 2 without operational components. A set of four rods 30, 32, 34 and36 are mounted on the interior bottom surface of the enclosure 11. Theserods project upward, perpendicular to the bottom surface of theenclosure 11. The top end of each of the rods 30, 32, 34 and 36 arethreaded to receive respective nuts 38, 40, 42 and 44. The nuts 38, 40,42 and 44, when mounted on the corresponding rods, engage the topsurface of a compression plate 51 shown in FIGS. 3 and 4 . The enclosure11 can include a thermostat and be connected to an air heater/cooler(see FIG. 8 ) to maintain the interior of the enclosure 11 within aselected temperature range to avoid thermal damage to the blood in theenclosure 11. Enclosure 11 has an opening 46 for passage of flow tubesand electrical cables.

A electric energy system of the present invention is shown in FIG. 1 ,and described in the corresponding text, with specific internalcomponents 50 of an operational unit 10 as shown in FIG. 3 . Theoperational unit 10 has multiple components 50 inside the enclosure 11.These components include the compression plate 51 and a light source 54.The unit 50 further includes a cassette 58 and an imager and processorunit 60. Line 22 extends through a pump 62 to the input of the cassette58. Pump 62 draws blood from patient 18 through input line 22 into theoperational unit 10 and the blood leaves unit 10 through return line 24and through catheter 20 back to patient 18. The components 54, 58 and 60have planar configurations and, in operation, are pressed together withlimited spacing between them and secured by the nuts 38, 40, 42 and 44to limit relative movement. The return line 24 is connected to theoutput port of cassette 58 and does not pass through the pump 62.

The compression plate 51 is shown in FIG. 4 . Plate 51 includes holes72, 74, 76 and 78 which are positioned to receive the respective rods30, 32, 34 and 36, see FIG. 2 . All of the elements 51, 54, 58 and 60are provided with colinear holes for receiving the rods 30, 32, 34 and36. When the nuts 38, 40, 42 and 44 are affixed to the rods 30, 32, 34and 36, with all of the noted components 50 (see FIG. 3 ) in place andhaving the rods 30, 32, 34 and 36 passing therethrough, the nuts aretightened on the rods to cause the compression plate 51 to apply forceto the stacked elements 51, 54, 58 and 60 to clamp them together andsubstantially limit relative movement, either horizontally orvertically, between these components.

A planar, bottom view of the light source 54 is shown in FIG. 5 . Source54 includes a 5×6 array 68 of light generators, which includes a lightgenerator 70 which is representative of all of the light generators inthe array 68. Each of the light generators, including 70, produces acollimated beam of light directed perpendicular to the cassette 58 andcovering an area. The light generator 70 is further shown in anelevation view in FIG. 6 . Light source 54 includes holes 71, 73, 75 and77 for receiving the rods 30, 32, 34 and 36.

Collimated light sources are well known in the art. Multiple embodimentsof collimated light source generators are usable with the presentinvention. Another collimated light generator is described in U.S. Pat.No. 7,758,208 issued Jul. 20, 2010 which patent is incorporated hereinby reference in its entirety.

The light generator 70, which is shown in FIG. 5 within an array of suchlight generators, is further described in FIG. 6 . The light generator70 includes a reflector 79 with an essentially parabolic shape andhaving an interior reflective surface 98. An LED 80 is mounted on aplatform 81 at the focal point of the reflector 79. An electricalconnector 82 is connected to the platform 81 and includes two conductivelines connected to provide electrical power to the LED 80. When power isapplied to the LED 80, light is generated around the periphery of theLED and is directed toward the reflective surface 98. The angle of lightgenerated by the LED 80 and the curvature of the surface 98 produce acollimated light beam 83. Such a collimated light source is shown inU.S. Pat. No. 7,112,916, which issued Sep. 26, 2006, and which patent isincorporated by reference herein in its entirety.

The cassette 58 is shown in an elevation section view in FIG. 7 .Cassette 58 comprises a top layer 136 and a bottom layer 138. Afterfabrication as separate layers, the layers 136 and 138 are bondedtogether to form the cassette 58. Both of these layers are made of anon-electrical-conducting material such as a polymer plastic.

The operational unit 10, shown in FIG. 1 , is further shown in FIG. 8with additional operational components. On the interior of enclosure 11there is the light source 54, cassette 58, imager and processor unit 60.Further included is a power supply 84 which receives power from line 16and provides power via power cable 85 to the processor unit 60 and tothe cassette 58. A temperature sensor 91 is mounted on the cassette 58to measure the temperature of the cassette 58. The temperature sensor 91is connected to the system controller 14 via a cable 94 to provide atemperature measurement of the cassette 58 to the controller 14. Thethermal control unit 26 is coupled by a cable 28 to the controller 14.The controller 14 measures the temperature of the cassette 58 by thetemperature sensor 91 and activates the thermal control unit 26 toprovide warmer air or cooler air to within the enclosure 11 via a duct27 to drive the temperature of the cassette to a selected temperature,for example, typical human body temperature.

The above embodiment in FIG. 8 has a power line that is directlyconnected to the cassette 58. An alternative configuration has a lightpower transmitter on the unit 60 for each chamber of the cassette 58. Inthis alternative configuration there is adjacent to each chamber of thecassette 58 a light power receiver that receives the light power beamfrom the underlying transmitter and converts the light power toelectrical power that is provided to a chamber driver 318 shown in FIG.21 . By use of the light power transmission, there is no requirement tohave any power electrical connection to the cassette 58.

The cassette 58 has an array of holding chambers. One embodiment of thecassette 58 has an array of 30 holding chambers, as shown in FIG. 9 .The cassette 58, as shown in FIG. 9 for an embodiment of the invention,has 30 holding chambers 184, 186, 188, 190, 192, 194, 196, 198, 200,202, 204, 206, 208, 210, 212, 214, 216, 218, 220, 222, 224, 226, 228,230, 232, 234, 236, 238, 240 and 242. The cassette 58 input manifoldcomprises distribution line 140 and chamber input lines 142, 144, 146,148, 150 and 152. The output manifold comprises chamber output lines158, 160, 162, 164, 166 and 170, the collection line 180 and the returnline 182. This manifold configuration provides approximately the sameblood flow path distance from the input of line 140 to the output ofline 182 for the blood flowing through each of the holding chambers. Thechambers and manifold lines are molded on the bottom side of the layer136. This configuration contributes to a more uniform flow of bloodthrough the holding chambers and more uniform fluid flow pressuregradient through the cassette 58.

Input line 142 supplies blood to each of the chambers 184, 186, 188,190, 192. Each chamber can have, for example, an X dimension of 2centimeters, a Y dimension of 2 centimeters, and a thickness (Zdimension) of 8 microns. The facing area of each chamber is therefore 4square centimeters. The opening width from the input line 142 intochamber 184 is the same as the Y dimension of the chamber, in thisexample, 2 centimeters. Likewise, the output from each chamber, such as184, is the Y dimension, in this example, 2 centimeters. A chamber, asviewed at the input, is relatively wide (2 centimeters) and relativelythin (8 microns). This configuration is the same for all of theremaining holding chambers in cassette 58. A selected spacing betweenthe interior surfaces of the chamber walls is 10 microns or less. Eachof the chambers has an input port and an output port. See FIG. 15 .Between the input line, such as 142, and the input port to a chamber,such as 184, there is a flow path having the same width and height asthe chamber and a length of, for example, 0.1 to 0.4 centimeters. Thereis a similar flow path at the output port of each chamber. See FIG. 15 .These flow paths assist in providing a uniform fluid flow through thechamber. These flow paths are shown in FIG. 15 as flow path regions 251and 253.

The blood leaves the holding chambers 184-242 and moves into thecorresponding connected chamber output lines 158-168. The exitpassageway from a chamber is the same configuration as the inputpassageway, that is, for this embodiment, the exit passageway is 2centimeters wide and 8 microns thick. The blood flows through the outputlines 158-168 into the collection line 180 and then into the return line182.

As a flow example, referring to FIG. 9 , blood is driven intodistribution line 140 and then into chamber input line 150 and at thefar end of this line, into chamber 232. After the blood is analyzed, theblood in chamber 232 is driven out of the chamber by pump 62 into thechamber output line 166 and from the end of line 166 into the collectionline 180. From line 180, the blood flows into the return line 182 andthen into the blood return line 24. The blood travels through thecassette input manifold to all of the chambers and returns from all ofthe chambers through the cassette output manifold.

Further referring to FIG. 9 , the cassette 58 is provided with alignmentholes 252, 254, 256 and 258. The cassette 58 is lowered onto thecorresponding upward facing rods 30, 32, 34 and 36, see FIG. 2 , mountedinside the operational unit 10, which pass through corresponding alignedholes in the imager and processor unit 60. See FIG. 3 . The rods passthrough the holes in the cassette 58 to provide alignment of thecassette 58 with the imager and processor unit 60. The light source 54(FIG. 3 ) has corresponding alignment holes to receive the rods 30, 32,34 and 36 so that the imager and processor unit 60, cassette 58, andlight source 54 are aligned with each other. The top ends of the rodsare threaded so that nuts 38, 40, 42 and 44 (See FIG. 2 ) can be appliedto each rod and tightened so that all three of these units arecompressed together and held in alignment with each other.

FIG. 9 shows a top, planar view of the top layer 136 of cassette 58.Each of the holding chambers 184-242 comprises a recessed region intothe bottom side of the top layer 136. Each chamber recess, in oneembodiment, is approximately 8 microns thick, 2 centimeters long and 2centimeters wide. Referring to FIG. 10 , each holding chamber includes aplurality of long, thin ridges 248, illustrated as horizontal lines ineach chamber in FIG. 9 , and shown in detail in FIG. 10 , which is asection view along line 10-10 of a representative holding chamber 196 inFIG. 9 . The ridges 248 are formed as a part of the upper layer 136.Example dimensions for a holding chamber and the ridges 248 are shown inFIG. The holding chamber 196 is approximately 2 centimeters wide, asshown, and 2 centimeters long, not shown. The ridges 248 extend for thelength (2 centimeters) of the holding chamber 196. Each ridge, in anembodiment, is, for example, 8 microns high and 4 microns wide. In thisembodiment, each of the holding chambers 184-242, has a thickness of 8microns. In this example, there are 20 of the elongate ridges spaced inparallel across a distance of 2 centimeters. Therefore, the spacingbetween the ridges is approximately 950 microns. Each of the ridges 248serves as a support for the bottom layer 138, see FIG. 7 , which ispressed against the top of the ridges 248 shown in FIG. 10 . The ridges248 also function as spacers to maintain an essentially uniform 8 micronthickness over all of the area of each holding chamber. The ridges 248,in this configuration, further form 21 flow channels through thechamber. These channels reduce the lateral flow of blood in a chamberand support a more straight-through fluid flow from the input to theoutput of each chamber. Each of the chambers has parallel, opposedtransparent walls.

FIG. 11 is a section view taken along lines 11-11 in FIG. 9 in thedistribution line 140. The distribution line flow channel has aflat-bottom with semi-circular cross section that has been pressed ormolded into the top layer 136. The flat, and sealing, surface of theflow line 140 is provided by the top surface of the bottom layer 138.FIG. 12 is a section view take along lines 12-12 in FIG. 9 located inthe input line 144. It is likewise pressed or molded into the top layer136 and covered with the bottom layer 138. The cross-sectional area ofline 144 at 12-12 is substantially smaller than that of line 140 at11-11. There is a greater volume of blood flow through line 14 at 11-11than through line 144 at 12-12.

All of the layers 136 and 138 are fabricated of, for example,transparent polycarbonate plastic, produced by a pressing or moldingprocess such as described in U.S. Pat. No. 6,998,076 issued Feb. 14,2006 which patent is incorporated herein by reference in its entirety.As an example embodiment, the top layer 136 can be approximately 2-3millimeters thick, bottom layer 138 can be 1-1.5 millimeters thick for atotal cassette 58 thickness of approximately 3-4.5 millimeters.

The top layer 136 of cassette 58 can be fabricated by the use ofpolycarbonate injection molding and a metal mold. An etched glass masteris used to form the metal stamping mold. To make the glass master, theprocess starts with a sheet of glass. The sheet of glass, approximately5 millimeters thick, is sequentially masked with photoresist patterns(as done in the manufacture of semiconductors) and an acid is applied toetch the non-masked portions. The acid removes a portion of the glass,producing a recessed pattern in the glass and forming the distributionlines and holding chambers. The final 8 micron etch can be done byplasma etching to produce more vertical sidewalls on the ridges 248.After removing the last photoresist, the surface of the glass mold istreated with a mold-release component, and then is covered with a layerof nickel or silver using an electrodeless plating method. Sputteringcan be used, or a colloidal silver method can be used. Then, nickel iselectroplated over the surface to a thickness of perhaps 0.5 cm forminga metal mold. After separating the electroformed nickel mold from theglass master, the metal mold has raised areas corresponding to thedistribution lines and holding chambers. This process is similar to themanufacturing process for phonograph records, compact discs and DVDs asshown in U.S. Pat. No. 6,998,076 noted above. Heated polycarbonateinjection molding is used with the metal mold to form the recessed flowchannels and holding chambers in what will be the top layer of thecassette. The polycarbonate flows around the raised areas in the metalmold. When the metal mold and polycarbonate are cooled, thepolycarbonate sheet is removed and it has the configuration for the toplayer 136, as shown in FIGS. 9-12 .

Alternately, a metal mold can be machined or etched to have theconfiguration to produce the cassette top layer 136 by applying a sheetof polycarbonate to the mold, heating both the mold and the sheet andallowing the polycarbonate to flow into the metal mold to produce thedesired shape for the cassette 58. The cassette 58 can be fabricated ofa plastic with an included anti-thrombogenic material to reduce thepossible adhering of blood that contacts surfaces of the cassette 58.Such a material is described in U.S. Pat. No. 6,127,507 issued on Oct.3, 2000, which patent is incorporated herein by reference in itsentirety. Alternatively, the anti-thrombogenic material can be appliedas a surface coating on the plastic.

FIG. 13 is an illustration of the cassette 58 together with theperistaltic pump 62 and the blood flow lines. The blood input line 22 ispositioned in the pump 62 between pump rollers 62 a and 62 b and acircular pump pressure plate 66. The rollers rotate about a center shaftand compress the line 22 against the interior curved surface of plate66. The rollers apply sufficient force to close the flexible line 22and, as they rotate, they force blood to flow through the line 22 towardthe cassette 58. The pump 62 can be started and stopped as needed topump blood to the cassette 58. After the blood has passed through thecassette 58, it flows through the return line 24 to the catheter 20 andthen back to the patient 18. The structure and operation of aperistaltic pump is well known in the art, particularly in the field ofkidney dialysis.

The flow of blood through the lines and chambers of the cassette 58 isshown in FIG. 14 . This is a top view of the layer 136. Blood enters theinput line 22 into distribution line 140 and is sequentially distributedinto the chamber input lines 142-152. Note that as the volume of bloodflowing through line 140 is decreased, the size of the line 140 iscorrespondingly decreased. Note that each of the distribution lines142-152 is tapered so the line size is decreased as the amount of bloodflowing in the line decreases. For example, blood flowing in throughinput line 22 has a portion thereof directed into distribution line 142and a portion of that flow enters holding chamber 186. As describedpreviously, the chamber 186 is approximately 8 microns high and thereare parallel ridges 248 that guide the blood in a uniform flow throughthe chamber 186. This substantially reduces transverse blood flow in achamber. At the exit of chamber 186, the blood enters output line 158where it joins the blood that has passed through chamber 184. The bloodfrom the chambers 184 and 186 flows through output line 158 and isjoined sequentially by the blood from chambers 188, 190 and 192. Theblood that has flowed through the chambers 184-192 then enters thecollection line 180. The blood from all of the holding chambers travelsinto the collection line 180 from which it flows into the cassette 58return line 182 to the blood return line 24. Each chamber has aninterior space between opposed walls.

Note in FIG. 14 that the configuration of flow lines and chambersprovides approximate the same travel distance for blood flowing througheach of the holding chambers 184-242. In each flow path, the blood flowsthrough or beside 10 holding chambers. For example, the blood flowthrough chamber 206 first passes chambers 184, 194 and 204 then flowsthrough chamber 206 and then passes chambers 208, 210, 212, 222, 232 and242, for a total distance of 10 chambers. This configuration of chambersand flow lines contributes to uniformity of blood flow and uniformity ofpressure gradient reduction for blood flow through the cassette 58.

Referring to FIG. 15 , there is shown a chamber 244, which isrepresentative of the chambers 184-242 described above. This chamber 244is in the bottom surface of the plastic body of the top layer 136 of thecassette 58. (See FIG. 7 ). The layer 136 has molded ridges 283 and 284,see FIG. 16 , which are shown as a group 248 in FIG. 10 . The chamber244 is subdivided into an identification zone 246 and a processing zone250. A region 271 of the processing zone 250 is shown in greater detailin FIG. 16 . A region 280 of processing zone 250 is shown in greaterdetail in FIG. 17 . An input port flow path region 251 transports bloodinto chamber 244 and an output port flow path region 253 receives bloodfrom chamber 244.

As shown in FIG. 15 , in operation, blood flows through an input lineinto the identification zone 246 where it is stopped and an image ofthis zone is produced by a light source which illuminates the chamberand cell shadow images are detected by a light sensor array on theopposite side. The data from the sensor array is electronicallyprocessed using a reference library of pathogen cells images to locatepathogen cells in the chamber identification zone 246. After thepathogen cells have been located in the channels of the chamber 244, atravel time is taken from a reference database table to specify thetravel time for each pathogen cell to the processing zone after the pumpis started. The pump is started and when each travel time in eachchannel elapses, a voltage is applied to electrodes in the sides of thechannel in the processing zone to apply electrical energy to thepathogen cell in the channel in the processing zone to neutralize thepathogen cell. The blood continues to flow through the processing zoneuntil all of the identified pathogen cells have passed through theprocessing zone. The blood flow is then stopped and the process isrepeated. Further structure of the processing zone is described below.

The region 271 of the processing zone 250 is shown in more detail inFIG. 16 . This view shows channels 272, 273 and 274. Channel 272 haselectrical insulating layers 275 and 276 on opposite vertical walls ofthe channel 272. Channel 273 has similar insulating layers 277 and 278.Insulating layer 277 covers conducting layer 287. Similarly, channel 274includes a single shown electrical insulating layer 279. The wall of thelayer 136 adjacent channel 272 has a planar conductive layer 285 betweenthe body of the layer 136 and the insulating layer 275. The ridge 283has a conductive layer 286 between the body of the ridge and theinsulating layer 276. The other side of ridge 283 has a similarconfiguration with a conductive layer 287 between the body of the ridge283 and the insulating layer 277. Ridge 284 has a similar configurationwith conductive layers 288 and 289. Channel 274 has a wall electricalinsulating layer 290 over conductive layer 289.

Referring to FIG. 17 , the conductive layers on opposite interiorsurfaces of the channels, for example, layers 285 and 286 at channel272, function as electrodes. When a voltage is applied between theseelectrodes, an electric field is established between the electrodes.This electric field has sufficient intensity to neutralize (kill) apathogen cell which is in the channel between the electrodes. Theinsulating layers over the conductive layers prevent the flow of anyelectrical current between the electrodes.

In further reference to FIG. 17 , there is a conductive pad 292 on thebase of the channel 272, the pad 292 being electrically connected to theconducting layer 285. A second pad 293 is electrically connected toconducting layer 286. An insulating layer 294 covers the pads 292 and293 to insulate these pads from the blood in the channel 272. Channel273 includes conductive pads 295 and 296 electrically connected torespective conductive layers 287 and 288. Pads 295 and 296 are coveredby an electrical insulating layer 297. Likewise, in channel 274, pads298 and 299 are connected electrically respectively to conducting layers289 and 290. Pads 298 and 299 are covered by electrical insulating layer305. Conductive layer 290 is covered by insulating layer 307. Theconductors, such as 285 and 289, have a length along the correspondingchannel 272, in the range of, for example, 10-200 microns.

When a voltage differential is applied between the pads 292 and 293, anelectric field is established between the conductive layers 285 and 286which are on opposite sides of the channel 272. Electrical fields aresimilarly established in channels 273 and 274 when an electrical voltagedifferential is applied to pads 295 and 296 and to pads 298 and 299.Each channel of each chamber has a similar conductive layer (electrode)configuration.

Referring to FIG. 18 , there is shown a section view of a chamber withridges, see FIGS. 16 and 17 , illustrating the components that provideelectrical connections from an electrical driver unit to the pads in thechannels. Two pads are described in detail and represent theconfiguration for the conductors for all of the pads. Pad 292 iselectrically connected to a through-hole conductor 309 to a surface pad311. A second through hole conductor and second surface pad (not shown)are electrically connected to the pad 293, and are located behind theconductor 309 and pad 311. Another example is a through-hole conductor313 connected electrically to pad 295 and a surface pad 315. Behind, inFIG. 18 , the conductor 313 and pad 315 is a corresponding conductor andpad for pad 296, see FIG. 17 . There are two through-hole conductors andcorresponding surface pads for each of the channels. Pads 311 and 315are included in a set of surface pads 317.

Further referring to FIG. 18 , there is a chamber driver 318, a packagedelectronic integrated circuit, which has a set of hemispherical pads 320including pads 322 and 324 which respectively align and are placed inphysical contact with pads 311 and 315. The pads in set 320 physicallyalign with and are set to be in electrical contact with the respectivepads in set 317. Driver 318 further includes a light receiver 348 andpower connection pads 349 and 350, which receive electrical power foroperating the driver 318. The light receiver 348 receives timing datafor operating the driver 318 for selectively applying voltages to thepairs of electrical layers in each of the channels.

FIG. 19 shows a group of the pads in set 320 including the pads 322 and324. FIG. 20 illustrates a group of the pads in set 317 including pads311 and 315. Pads in set 317 are fabricated on the top surface of thelayer 136. Pads in set 320 are fabricate on the bottom surface of thedriver 318. Driver 318 is mounted on the top of layer 136 so that thepads on the driver in set 320 match up one-to-one with the pads in set317.

An electrical block diagram of the driver 318 is shown in FIG. 21 .Driver 318 is preferably a packaged integrated circuit. The driver 318includes the light receiver 348 which receives pulsed light from anassociated processor, described below, with data defining the amplitudeand voltages to be applied to the electrodes (conducting layers) in eachof the channels in the associated chamber. The light receiver 348provides a received signal via a line 351 to a data receiver 352. Thedata receiver 352 provides a digital data stream via a line 353 to aprocessor 354. The processor 354 is coupled via a bus 355 to amultiplexor/driver 356. Driver 356 is electrically connected to the padsin the set 320. Power pads 349 and 350 are connected to a power receiverand power driver 357. Pads 349 and 350 are connected to the power supply84 (See FIG. 8 ). The power receiver and power driver 357 provideselectrical power to the data receiver 352 via a line 359, to the lightreceiver 348 via a line 361, to the processor 354 via a line 363 and tothe multiplexor/driver 356 via a line 365.

An alternate configuration to that shown in FIGS. 16 and 17 is shown inFIGS. 22 and 23 . The structure shown in FIGS. 22 and 23 is the same asthat in FIGS. 16 and 17 with the exception that the insulating layersare not present over the conductive layers that are on the opposingwalls of each channel. The absence of the insulating layers places theconductive layers, such as 285 and 286 which are on opposite sides ofchannel 272, in electrical contact with the fluid in channel 272. Thiscreates a flow of electrical current through the blood fluid. Blood iselectrically conductive and has resistivity.

FIG. 24 is an electrical block diagram of the system shown in FIG. 1with detailed structure shown for the imager and processor unit 60. Theunit 60, in one embodiment, includes a printed circuit board withcomponents mounted on it. The system controller 14 (See FIG. 1 ) iscoupled via a cable 12 to the unit 60 by use of a connector 391 and acable 392 to a master controller 434. The controller 434 can be, forexample, a microprocessor, a dedicated gate array or other processingdevice. The controller 434 can activate and deactivate the light source54 and pump 62 via the cable 12. The master controller 434 is connectedvia a cable 393 to an input/output (I/O) multiplexor 394. Themultiplexor 394 is connected to each of a plurality of assemblies 395.In an embodiment, there is one of the assemblies 395 for each of thechambers of the cassette 58, such as the 30 chambers 184-242 shown inFIG. 9 . The master controller 434 can communicate via the multiplexor394 to each of the assemblies 395 and can receive communication fromeach of the assemblies 395. Each assembly 395 includes a light sensor260 which is positioned below and aligned with a corresponding chamberin the group of chambers 184-242. Each light sensor 260 is a lightsensor array of pixels. See FIG. 25 . The multiplexor 394 communicateswith the assembly 395 via cables 396, 397 and 398. There is a similarset of cables, such as printed circuit board traces, for each of theother assemblies in the unit 60.

Further in reference to FIG. 24 , each assembly 395 includes a memory399 which receives from the light sensor 260 digital data via a cable400 comprising data and control lines (See FIG. 25 ). When the lightsensor 260 has received light and has a data state for each pixeltherein, this data can be transferred to the associated memory 399. Eachassembly 395 further includes a chamber processor 401 which has a databus 403 and control line 407 coupled to the memory 399. The processor401 can command that part or all of the data in memory 399 betransferred to the processor 401 to be processed. The master controller434 communicates via the multiplexor 294 via cable 396 to the chamberprocessor 401, the cable 397 to the light sensor 260 and cable 398 tothe memory 399. Each assembly 395 further includes a light datatransmitter 409, for example a modulated laser beam generator, connectedvia a data transmission and control cable 411. The light datatransmitter 409 sends data and control commands to a correspondingchamber driver 318. See FIG. 21 .

An example light sensor array integrated circuit for use with thepresent invention is shown in FIG. 25 . A sensor array 260 includes anarray 262 of individual pixel cells, each pixel further described below.Surrounding the array 262 of pixel cells is circuitry termed control andI/O (Input and/or Output) 264 which controls the operation of the sensorarray 260 and the transfer of pixel data collected by the sensor array260. A group of data lines 266, for example 16 parallel lines, transferspixel data from the pixel array 262 to an associated memory. A set ofcontrol and power lines 268, for example 8 lines, controls the operationof the sensor array 260 and provides power for operation of the sensorarray 260 circuitry. As further described below, the sensor arrayreceives a reset signal to set an initial charge state in each of thepixels. When the pixels are exposed to light, each pixel is dischargedfrom the initial state to a final state (the pixel data) depending onthe amount of light that was received by the pixel. A command is sentthrough lines 268 which causes the sensor array 260 to transfer thecollected pixel data through one or more of the lines 266 to anassociated memory.

As an example, the pixel array 262 can have a pixel size of 0.50 micronby 0.50 micron (square configuration) and the light sensitive array hasa size of 2 centimeters by 2 centimeters. If there is only one bit perpixel, either light or dark, the pixel data for one image is the size ofthe number of pixels. These dimensions are exemplary only, and a sensorarray larger or smaller than array 262, as presented, may be used.

A partial section, top view of the pixel array 262 is shown in FIG. 25 .This illustration, for a design having the dimensions listed above, of apixel array includes a dimension scale in microns. This top left cornerof the array 262 shows individual pixels, each a square having sidedimensions of 0.5 micron. A single pixel, such as 270 is representativeof all of the pixels in the array 262.

A circuit for each of the pixels, such as 270, in the array 260, can beany one of many types. A 3-T (three transistor) pixel circuit is shownin FIG. 26 and a 4-T (four transistor) pixel circuit is shown in FIG. 27.

Referring to FIG. 26 , a 3-T pixel circuit 300 includes a photodiode(PD) 302, a transfer transistor 306, a reset transistor 304, a drivetransistor 308 and a floating diffusion (FD) 310. A reset signal (RS) issent through a line 314 to the gate of reset transistor 304. A transfercontrol signal (TG) is provided through a line 316 to the gate oftransistor 306. The image data produced by pixel circuit 300 istransmitted through column line 312.

In operation, the pixel circuit 300 is initially reset by turningtransistor 304 (RX) on to charge node FD 310 to VDD. Next the TG signalturns on TX transistor 306 which couples the node FD to the cathode ofphotodiode 302. Upon receiving light at the photodiode 302, the diodereverse conducts and discharges node FD dependent upon the amount oflight received by the diode. The charge on node FD drives the transistor308 (DX) which applies a corresponding current to the column line 302.

A 4-T pixel circuit 326 is shown in FIG. 27 . This circuit has aphotodiode (PD) 328, a reset transistor 330 (RX), a transfer transistor332 (TX), a drive transistor 334 (DX), and a select transistor 336 (SX).A floating diffusion 338 (FD) is connected to the gate of transistor334. Transistor 330 (RX) receives a reset signal through line 342.Transistor 332 (TX) receives a drive signal (TG) through a line 344.Transistor 336 (SX) receives at its gate a select control signal (SEL)via a line 346.

The pixel data, which is the measured light, is sent through the columnlines 312 and 340 in FIGS. 26 and 27 . At the end of these lines thereis an analog to digital converter to produce a high or low, 1 or 0,digital signal. This is essentially a threshold detection. Each pixeldata represents dark or light, depending on how much light was receivedat the pixel.

Operation of the pixel circuit 326 (FIG. 27 ) begins with receipt of areset (RS) signal at transistor 330 to charge node FD 338 to VDD. Next,the transfer control signal (TG) turns on transistor 332 to couple thecathode of photodiode 328 to node FD. When the photodiode 328 receiveslight, charge is drawn from node FD to reduce the voltage on node FD,which drives the gate of transistor 334 (DX). For readout of data fromthe pixel, signal SEL is applied to turn on transistor 336 (SX) tocouple transistor 334 (DX) to the column line 340. The column line 340is sequentially used to transfer data from all of the pixels connectedto the column line.

FIGS. 28 and 29 illustrate a physical integrated circuit structure forimplementing the 4-T pixel shown in FIG. 27 . Layout 358 in FIG. 28 is atop view. A unit pixel area 362 is the area occupied by the pixelstructure. A deep trench isolation (DTI) region 364 serves to isolateeach pixel from surrounding pixels. Active area 366 is the area of thepixel which receives light. A shallow trench isolation (STI) 368separates active elements of the pixel. First border 370, second border378 and third border 380 serve to isolate elements of the pixel circuitto reduce noise. 372 is a ground element. 374 is a transfer gate. 376 isa floating diffusion. 382 is a p-well. 384 is a p-well. 386 is the drivetransistor gate. 388 is the select transistor gate and 390 is the resettransistor gate.

FIG. 29 is a section view layout 402 along line 29-29 of the structureshown in FIG. 28 . The common elements in FIGS. 39 and 401 have the samereference numerals. Element 404 is an oxide isolating layer, 405 is aborder, 406 is a polysilicon isolation layer and 410 is a photodiode inconjunction with the epitaxial layer 412. Element 414 is ananti-reflection layer. 420 is a gate isolation layer. 424 is a floatingdiffusion (FD 338 in FIG. 27 ). Light, shown by the upward pointingvertical arrows in FIG. 29 , produced by the light source 54 in FIG. 3 ,is transmitted to the pixel structure and in particular to thephotodiode for measuring the light received by this one pixel.

Referring to FIGS. 30, 31 and 32 , there is shown a physical calibrationfor the alignment of a cassette chamber with the underlying lightsensor. A segment 416 of a chamber, such as any of chambers 184-242(FIG. 9 ) is subdivided into a set of areas, which, in this example,each area has a size of 100 microns by 100 microns. Area 418 is near thecorner of a cassette chamber, and FIG. 31 illustrates a middle region ofthe area 418. A light blocking calibration marker 419 is positionedapproximately in the middle of area 418. The upper left corner of themarker 419 is at the position of 150 microns horizontal and 150 micronsvertical. The marker 419 is printed on the interior surface of thecassette chamber. The marker, in this example, has a unique L-shape—itis 2 microns long, 1 micron wide and the body is ½ micron wide. Thisshape can be readily identified in pattern recognition. FIG. 32illustrates a region of the light sensor beneath the chamber having themarker. If the chamber and underlying light sensor were perfectlyaligned, the shadow image of the chamber marker 419 would be at the sameposition in the light sensor, as shown by the dotted marker outline 421.But, if the chamber and light sensor are not in perfect alignment, themarker 419 could produce a shadow image 423 which is offset from thedotted marker outline 421. In the illustrated example, the shadow image423 is offset by 6 microns to the right and 8 microns down. Thus, forthe area 418, the alignment correction is (−6, −8). Thus, for any imagein the 418 area for the light sensor, the position determined in thelight sensor is adjusted by −6 microns horizontally and −8 micronsvertically. Each of the areas of the cassette chamber is provided with aprinted marker, such as 419 and the shadow image of each marker in thelight sensor is determined. A physical calibration table is preparedhaving the correction numbers for each area of the cassette chamber.

Referring to FIGS. 25 and 31-32 , the sensor array can be divided intocalibrations zones. For a 2 cm by 2 cm sensor array, each calibrationzone can be, for example, 100 microns by 100 microns. With these sizes,the array 262 has 4×10⁴ calibration zones. If the calibration zone islarger, there will be fewer calibration zones in the sensor array. Eachcalibration zone can be calibrated, as described, and the calibrationvalues can be different between calibration zones. This will compensatefor nonlinearities across the sensor array 262.

In a summary of system operation, the controller 434 drives the pump 62to fill the holding chambers in a cassette 58 (See FIGS. 3, 14 and 124 )with blood. When the holding chambers are filled, the pump is stopped.The controller then sends a reset command to each sensor array to resetall of the pixels in each array. Next, the controller sends anactivation command to all pixels in all sensor arrays. After this, thecontroller 434 activates the light generator 54 to produce visible lightfor a set period of time. When this time has elapsed, the controller 434sends a control signal to all pixels in all sensor arrays to endactivation. Next, the controller 434 sends a command to each sensorarray 260 to download the collected pixel data to the correspondingmemory 399. After the pixel data has been loaded in the memories, thecontroller 434 commands each of the chamber processors mounted on board432 to process the pixel data in the corresponding sensor array forpattern recognition using an image library to identify and locate theimaged pathogen cells. Each processor determines, after applyinglocation correction factors if required, the location in the chamber foreach identified pathogen cell image. The chamber processors send to thecorresponding chamber drivers the location of each identified pathogencell. The driver has a travel time table with values for each zone ofeach channel in the chamber. The controller 434 starts the pump 62 andsends a start command to all of the chamber processors which then send astart command to the chamber drivers which generate a drive voltagesignal to the opposing conductors in each channel when each travel timeexpires for a detected pathogen cell thereby applying electrical energy(field or current) to the specific located pathogen cell. When thetravel times have been completed, the controller 434 stops the pump 62and the process of identification, fluid flow and generation of voltagesignals is repeated.

The chamber processors described herein, one used with each sensorarray, can be, for example, a microcomputer, a graphic processor or acustom gate array. The master controller can be, for example, amicrocomputer or a custom gate array.

The 30 sensor arrays (See FIGS. 9 and 24 ) each align with a holdingchamber in cassette 58. There is a one-to-one relationship. For example,holding chamber 184 (FIG. 9 ) is positioned over and aligned with alight sensor such as 260 (FIG. 24 ). Each of the remaining holdingchambers (FIG. 9 ) of the cassette 58 is likewise located over andaligned with a sensor array (See FIG. 24 )

Operation of the apparatus described herein can include an initialcalibration of the light energy produced from the light source 54 to besufficient to activate the individual pixels in the light sensors 260shown in FIG. 24 . Also referring to FIG. 3 , as directed by the mastercontroller 434 after receiving an energy calibration command from thesystem controller 14, the energy calibration process first resets all ofthe pixels in all of the sensor arrays 260. Next, it activates all ofthe pixels in all of the sensor arrays and then activates the lightgeneration from the light generator 54 for a selected time. The pixelsin the light sensors are then deactivated, the pixel data transferred tothe corresponding memory and the processor activated to run a lightenergy calibration routine. If the light energy is sufficient, all ofthe pixels will be light, that is, no dark pixels since there is nothingin the cassette holding chambers during this calibration process. Themarkers in the chambers are excluded. The processor counts the number ofdark pixels. The master controller polls all of the chamber processorsto collect the number of dark pixels. If the number of dark pixelsexceeds a preset threshold, such as 0.001%, the calibration process isrepeated and the selected time is incrementally increased until thenumber of dark pixels is less than the preset threshold. If the initialmeasurement shows the number of dark pixels to be less than the presentthreshold, the process is repeated with shorter light activation timesuntil the threshold is crossed and the last lower value is selected asthe light activation time. The light energy can be varied by changingthe length of time the light is on, or by varying the intensity of thelight. In either case, a light activation value, either time orintensity, will be produced.

Light energy calibration can also be performed after the blood holdingchambers have been filled as shown by the steps in FIGS. 33A and 33B.The system controller initiates the filled chambers light energycalibration process by sending a command to the master controller 434.See step 568. Referring to FIG. 24 , the controller 434 drives the pump62 to fill the holding chambers in cassette 58 (FIGS. 3 and 9 ). Seestep 570. Next, in step 572, the controller 434 sends a reset command toeach of the light sensors 260. After the pixels in each sensor arereset, the controller 434 commands (step 573) each light sensor array tobe activated. Next, in step 574 the light generator 54 is activated fora period of time X. The controller 434, in step 575, deactivates all ofthe light sensor arrays, and in step 576 commands each sensor array todownload its pixel data to the corresponding memory. Next, in step 577,the controller commands each chamber processor associated with a sensorarray to (step 578) access the pixel data in the corresponding memoryand perform a light calibration process in which the number of lighttransitions between adjacent pixels is counted. The transition can beeither light to dark or dark to light. Each pixel has four adjacentpixels and each possible transition is examined. For example, a darkpixel surrounded by four light pixels produces four transitions. In step588, the controller 434 then collects the pixel transition count fromeach processor and adds them together to produce a total transitioncount corresponding to the period of time the light generator was on. Instep 589, the master controller produces a table of light durations asshown below in Table 1. Next the above process is repeated with anincrementally longer period of time for the operation of the lightgenerator. The number of transitions for this period is determined andrecorded. Next, in question step 590, it is determined if the peak valueof the number of light transitions has been passed. This is selected,for example, by having 100 sequential transition counts lower than apreceding transition count. If the response to question step 590 is“NO”, in step 592, the value of X is increased by a selected increment,and control is returned to step 571. This process is repeated until apeak of transition number is reached, as noted. If the response toquestion step 590 is “YES”, the master controller 434, in step 594 sendsthe completed table of light duration and count of pixel transitions tothe system controller 14. This calibration process terminates at STOPstep 596. An example of such data is as follows. The light energy valueis a relative measure and the Pixel Transitions number is a truncatedvalue, such as billions of transitions.

TABLE 1 Relative Light Energy Pixel Transitions 1 50 2 65 3 85 4 100 5120 6 140 7 150 8 165 9 160 10 150 11 135 12 125 13 115 14 105 15 90

As seen in the above data listing, the optimum light energy value is “8”which corresponds to the pixel transition value “165”. The number ofpixel transitions is an indicator of the quantity of image informationpresent in the pixel data and is likely the best image data. Therefore,for this instance of testing, the light energy should be set to therelative level of “8” for the process described herein to identify andlocate pathogen cells in the blood. As noted above, the light energy canbe varied by time duration or by the intensity of the light produced.

A pathogen cell, together with a measurement scale, is shown in multiplepositions in FIG. 34 . E. coli is a rod-shaped bacterium. The dimensionsfor this bacterium can vary but some species can be in the range of 2-3microns long and 0.25 to 1 micron thick. In FIG. 34 , there is shown inthe left column an e. coli bacteria cell 600. The left column shows anactual view of a cell and the two right columns show shadow images thatcan be produced by that view of the cell by the sensor arrays (FIG. 25). These views are based on a system as described with 0.50 micron by0.50 micron sensor array pixels. The right two columns show shadowimages produced by the corresponding cell in the left column. The cell600 is shown at multiple rotations along a vertical axis with angles of0, 15, 30, 45, 75 and 90 degrees. These multiple views are requiredbecause the cell could be at any rotation position as it is viewed in aholding chamber. The right two columns (a) and (b) represent possiblevariations on the image produced by the cell positioned at the indicatedrotation. Images 602 and 604 can be produced by cell 600 at rotation of0 degrees. These can differ due to edge effects and small thresholddifferences in pixel sensors. Images 606 and 608 could be produced forrotation 15 degrees, 610 and 612 for rotation 30 degrees, 614 and 616for 45 degrees, 618 and 620 for 60 degrees, 622 and 624 for 75 degreesand 626 and 628 for 90 degrees. The images 602-628 are the image libraryfor the pathogen cell 600. These images are the search targets in thepixel data for identifying and locating the pathogen cells. These imagescan be located in the pixel data by the use of pattern recognition.Pattern recognition for detecting predetermined images in a digital datafield is well-known technology. An example patent describing suchtechnology is U.S. Pat. No. 9,141,885 issued Sep. 22, 2015 which patentis incorporated herein by reference in its entirety.

Referring to FIG. 35 , there are shown views of corresponding shadowimages of red blood cells, which comprise the majority of cells in humanblood. The size of red blood cells can vary, but can be in the range of6-8 microns. In FIG. 35 , left column, there is shown a red blood cell638. A red blood cell has a disc shape with a flattened center where thethickness may be 1-2 microns. Cell 638 with a rotation of 0 degrees canproduce the shadow image 638, with rotation 45 degrees the shadow image640 and with rotation of 90 degrees the shadow image 642. These imagesare included in the image library as being images to be ignored sincethey are different from the bacteria or other pathogen images that aresought to be found.

FIG. 36 shows a white blood cell 648 having a relatively large size anda white blood cell 650 having a smaller size. These cells areessentially spherical so appear approximately the same at all rotationangles. Cell 642 can produce a shadow image 652 and cell 650 can producea shadow image 654. Again, these images 652 and 654 can be included inthe cell library as images to ignore.

A blood platelet cell 660 is shown in FIG. 37 . A platelet is a biconvexdiscoid (lens-shaped) structure, 2-3 micron in greatest diameter. Thisshape is thin at the edge and thickest in the center. At a rotation of 0degrees, the cell 660 can produce a shadow image 662, at a rotation of45 degrees a shadow image 664 and at 90 degrees, a shadow image 666. Aswith the other normal blood cells, these images are used as recognitionof cells to ignore in the processing operation.

Each of the cells in FIGS. 35, 36 and 37 are shown, for illustration, ata limited number of rotation angles; but the library can contain imagesrepresenting a finer degree of rotation, for example, every 5 degrees ofrotation.

The operation of the present disclosure in summary includes initiallydetermining the static position of each pathogen in a channel in thecassette chamber. Next, the pump and a travel time timer are startedsimultaneously. The pump operation causes the pathogen cell to move fromthe initial location toward the processing zone of the chamber. When thetravel time expires, the pathogen is located in the destruction regionof the processing zone, the region having electrodes of opposite sidesof the channel. When the travel time expires, the chamber drivergenerates a voltage waveform that is applied to the opposing electrodesin the processing zone and this action applies electrical energy to thepathogen cell. The applied electrical energy is sufficiently great toneutralize the pathogen cell located between the electrodes. Theelectrical energy can be applied as a field or current. One method ofdetermining the travel time between the identification zone and theprocessing zone is described in reference to FIGS. 38 and 39 and thelogical flow diagram for this process is shown in FIG. 40 .

Referring to FIGS. 38 and 39 , there is shown a representative channel426, corresponding to each of the channels shown in the chamber in FIG.15 . The channel 426 is divided into a plurality of sequential andcontiguous channel zones, including exemplary channel zones 427, 428,429 and 431. As an example, the channel 426 can be 8 microns wide andeach zone is 6 microns long. The channel zones do not have any physicalstructure marking the position of each zone, but are defined bylongitudinal position. If, for example, a channel is 2 centimeters long,it will have approximately 3333 channel zones. The channel 426 furtherincludes arbitrarily defined sets of channel zones identified as a firstwindow 433 of zones and a second window 435 of zones. An approximationof the flow rate of blood through the channels in the chambers of thecassette 58 can be calculated using the flow rate of the pump 62 and thegeometry of the flow lines and chambers of the cassette 58. The channelzone 427 is selected to be near the input of the chamber. The locationof the first window 433 is determined by use of the calculatedapproximate fluid flow rate of blood in a chamber and is sufficientlywide to accommodate the possible error in that flow rate. The secondwindow 435 is set at a predetermined distance from the first window 433.A processing zone in channel 426 corresponds to the processing zone 250in FIG. 15 . The opposed electrodes, see FIG. 16 on the sides of thechannel define the processing zone and the length of this zone should berelatively short to have shorter electrodes and therefore moreconcentrated electrical energy applied to the fluid in the channel. Theflow rate calibration process described in FIGS. 38 and 39 can moreaccurately establish the total travel time from each of the channelzones, where a pathogen cell is initially located, to the processingzone as compared to a flow rate determined by only pump rate, tubing andcassette geometry.

Referring to FIG. 39 , there is shown a chart of flow rate of fluidversus time. The pump starts at time t₁ where the fluid velocity iszero. After the pump starts, the fluid velocity increases until itreaches a constant velocity. This is shown as v₁. Depending on physicalconfiguration, the time to reach constant velocity could be, forexample, approximately 0.01 to 0.02 seconds. A time T1 is selected whichis larger than the time for the fluid to reach constant velocity. A timeT2 is selected which, when added to time T1, is the approximate traveltime from the zone 427 to the second window 435. The total travel time,from zone 427, to the center of the processing zone 437 is TTi, the “i”representing each zone.

The calibration process, shown in FIGS. 38 and 39 , is described indetail in the logic diagram in FIG. 40 . In summary, the process beginswith pumping fluid into the chambers of a cassette and then stopping thepump. The light sensor below a chamber is activated and the light sourceis turned on the illuminate the chambers. Pathogen cells in the channelsof the chamber create shadow images in the pixels of the light sensor.The data from the light sensor is stored in a corresponding memory. See.FIG. 24 . The data is evaluated by a corresponding processor usingpattern recognition to identify and locate pathogen cells, such as cell439 in channel zone 427. The pump is activated and when the cell 439 isin the first window 433, the light sensor is reset and the light sourceis activated for a short flash, for example a millisecond or less, andthe shadow image is created in the corresponding light sensor. The pixeldata is processed by the corresponding chamber to identify and locatethe cell 439, which as shown, is located in channel zone 429. Thelocations of zones 427 and 429 define the distance D1. The fluid ismoving at the constant velocity when the cell is imaged at zone 429, butthe light flash is of sufficiently short duration, as compared to theflow rate, that there is a clear image of the cell. This is essentiallya “stop image” shot. The fluid continues to move until the pathogen cellis in the second window 435 where another flash shot image is taken asjust described. The cell 429 is then determined to be in channel zone431.

Further referring to FIGS. 38 and 39 , the distance between zones 429and 431 are predetermined parameters. T1 and T2 and distance Dt (foreach channel zone) are predetermined. T1 is selected to be less than thesmallest total travel time. T3 is the flow time from the end of time T1to the cell 439 arrival at the center of processing zone 437. D3 is thedistance from zone 429 to the center of zone 437. The total traveltravel time from a channel zone to the center of the processing zone isTTi. The constant velocity fluid flow rate (Vcv) between zones 429 and431 is determined by the equation: Vcv=D2/T2. Therefore, the totaltravel time (TTi) from any channel zone to the center of the processingzone 437 is: TTi=T1+T3; T3=D3/Vcv, and therefore:

TTi=T1+(Dt−D1)(T2/D2).

Thus, after the calibration process described above has been performedfor a channel in a chamber, the total travel time TTi can be calculatedfor each channel zone (i) in the identification field of the chamber.The term Dt is different for each channel zone in a single channel.Further, the same calibration process is performed for all of thechannels in all of the chambers. A calibration table is prepared foreach chamber that provides the travel time from each channel zone to thecenter of the corresponding processing zone. In operation, after apathogen cell is identified in the detection zone and located in aspecific channel zone, the pump is started and the pathogen cell movestoward the processing zone and when the total travel time, for thatspecific channel zone, expires, the pathogen cell is located in theprocessing zone. At that time, a voltage is applied to the electrodes inthe processing zone to neutralize the pathogen cell as it passes throughthe processing zone. In this process, the fluid flow is continuous afterthe pathogen cell has been initially identified and located. After theblood in the chamber has been replaced, the pump is stopped and theprocess is repeated.

A logic flow description of the calibration process is shown in FIGS.40A, 40B and 40C. The calibration process is begun at step 446 at thesystem controller 14. The calibration parameters and data are the pumpdrive time to fill the chambers, for example 15 seconds, first andsecond light source activation times LSRC1 and LSRC2. Values of thesetimes can be, for example, respectively 1 second and 1-5 milliseconds.The cell library is the collection of pathogen images described above.The estimated travel times can be, for example T1=1-2 seconds andT2=4-10 seconds. The start calibration command and the calibrationparameters are downloaded to the master controller 434 from the systemcontroller 14 in step 448.

Continuing reference to FIG. 40A, in step 450, the master controller 434starts the pump 62, runs the pump for the fill time and then stops thepump. Next, in step 452, the master controller 434 resets all of thelight sensors so that they are prepared to receive light from the lightsource 54. In step 454, after the light sensors are reset, the mastercontroller 434 activates the light source 54 for the time period LSRC1and the light sensors receive light after it has passed through thechambers and shadow images of cells in the chambers are created in thepixel data in the light sensors. In step 456, after expiration of thetime period LSRC1, the master controller 434 transfers the image datafrom the light sensors to the corresponding memories. See FIG. 24 . Instep 457, the chamber processor, for each chamber, processes the imagedata by performing pattern recognition with the cell library to identifypathogen cells in the channel zones. In step 458, the chamber processorselects one located pathogen cell for the calibration process. Thespecific location zone for this selected cell is identified.

In step 460, the master controller 434 resets all of the light sensors.See zone 427 in FIG. 38 . Next, in step 462, the master controllerconcurrently starts the pump 62 and a calibration timer to runsequential times T1 and T2. At step 463, upon expiration of time T1, thelight source 54 is activated for time period LSRC2. This takes a “stopaction” image of cells in the channels in the first window 433. Thefluid flow rate is slow in comparison to the on time of the light sourceso that a clear image is produced without stopping the fluid flow. Atstep 464, after the time LSRC2 has ended, the master controller 434transfers the pixel data from each light sensor to the correspondingmemory. In step 465, the chamber processors process the image data inthe corresponding memories using the cell library and patternrecognition to identify and locate the cell previously identified in thechannel at the initial channel zone. In step 466, the chamber processordetermines the distance D1 which is between the initial channel zonelocation and the identified location in the first window 433.

In step 467, the master controller 434 resets all of the light sensors.Next, in step 468, when the time period TG2 expires, the mastercontroller activates the light source 54 for the time duration LSRC2. Instep 469, when the time period TG2 has expired, the master controllertransfers the collected pixel data from each light sensor to thecorresponding memory. In step 470, the chamber processors performpattern recognition on the pixel data for pattern recognition and usingthe cell library as reference data, to locate the previously identifiedpathogen cell previously identified in the first window. Next, in step471 the chamber processor determines the distance D2 which is thedistance between the identified cell locations in the first and secondwindows. In step 472, the master controller 434 stops the pump.

In the next step 473, the chamber processor calculates the fluidvelocity between the two locations in the windows, using distance D2 andtime T2. See FIG. 38 . With this data the chamber processer determinesthe total travel time TTi for each channel zone (i) to the center of theprocessing zone. The travel times are determined for all channels ineach chamber. In step 474, the chamber processors transfer the totaltravel time table of values for each chamber to the master controller434. In step 476, the master controller transfers all of the travel timetables for all of the chambers to the system controller 14 and reportscompletion of the calibration process. In step 478, the systemcontroller 14 displays an end of calibration report on its displayscreen and ends the calibration process.

By closely calibrating the travel time of each initially detectedpathogen cell to the center of the processing, the length of theprocessing zone can be limited so that the maximum electrical energy canbe applied to the pathogen cell in the processing zone and less bloodfluid is exposed to the electrical energy. If the predicted total traveltime number were to be less accurate, the electrodes in the processingzone would need to be longer to assure that the pathogen cell is in theprocessing zone when the electrical energy is applied.

An operation process for an embodiment of the present invention is shownin the logic flow in FIGS. 41A, 41B and 41C. This process utilizes theapparatus shown and described in the prior text and figures. The processbegins with a start command, for example from an operator, at the systemcontroller 14 in step 480. The system controller 14 downloads data andprocessing parameters, step 482, and a start command is sent to themaster controller 434. The processing data and parameters include:

-   -   1. Pathogen image cell library.    -   2. Initial pump flow time and pump cycle on and off times. This        can be, for an example, an initial flow time of 20 seconds to        completely fill all of the chambers. After the start, a flow and        processing time of 10 seconds with a stop time of 2 seconds for        initial identification of pathogen cells. The 2 second stop with        10 second flow is repeated until the processing is completed.    -   3. A light generation time, for example, in a range of 20 to 100        milliseconds.    -   4. A light sensor collection time of, for example, within a        range of 5 to 50 milliseconds.    -   5. Voltage waveforms for application to the processing zone        electrodes    -   6. Alignment data for each sensor array.    -   7. Travel Time Table for each channel of each chamber.    -   8. Total processing time, for example, in the range of 6-24        hours.

In step 484, the master controller 434 sends certain data and processingparameters to the chamber processors. This includes the pathogen imagelibrary, the voltage waveforms for the channel electrodes in theprocessing zone, the alignment data for sensor arrays and the totaltravel time tables for each chamber. In step 486 the voltage waveformsand travel time tables are transferred from the chamber processors tothe chamber drivers for each chamber.

In step 488, the master controller 434 runs the pump for the initialpump flow time to fill the chambers and then stops the pump. The mastercontroller 434 also starts a total processing time timer. In step 490,the master controller resets all of the light sensor arrays so they areprepared to receive light. In step 492, the master controller 434activates the light source 54 for the light generation time. Next, instep 494, the light sensors are activated to collect light for the pixellight collection time. In step 496 the collected pixel light data istransferred from the sensor arrays to a corresponding memory. In step498, the master controller 434 commands each chamber processor toperform pattern recognition on the stored pixel data using the pathogencell library and to locate each identified pathogen cell. In step 500,each chamber processor performs the pattern recognition and generates alisting of the pathogen cell locations in each channel of thecorresponding chamber. Each identified pathogen cell is in a channelzone, see FIG. 38 , for example zone 428. The chamber processor alsoadjusts for any misalignment between cassette and sensor array with thealignment data. In step 502 each chamber processor, by use of thedownloaded travel time table, determines the total travel time for eachidentified pathogen cell from its identified channel zone location tothe center of the processing zone.

Further referring to FIG. 41B, in step 504 the determined travel timesfor each identified pathogen cell and the corresponding channel istransferred to the corresponding chamber drivers. This data transfer isdone via the optical link from the chamber processor to the chamberdriver, see FIG. 24 , light transmitter 409 and FIG. 21 , light receiver348. In step 506 in FIG. 41C, the master controller 434 receives thedata transfer completion reports for all chamber processors and thenactivates the pump 62 and sends chamber driver activation commands toall of the chamber processors. In step 508, the chamber processors sendactivation commands to the corresponding chamber drivers. In step 510,in response to the activation command, each chamber driver starts thetiming for the total travel times for the identified pathogen cells ineach channel. When a total travel time is completed for a channel, thecorresponding chamber driver generates voltage waveforms which areapplied separately to the electrodes in that channel in the processingzone, for example, electrodes 285 and 286 shown in FIG. 16 . In FIG. 42there are shown waveforms 512 and 513. These waveforms are shown as afunction of time “t” along the horizontal scale. The peak positive valueis +V and the peak negative value is −V. When the total travel time hasexpired for a channel, the driver 318 (FIG. 18 ) applies waveform 512 toone electrode, such as 285 and applies the second waveform 513 to theother electrode 286. Because these waveforms are inverses, the voltagedifference between the electrodes is 2V.

Referring to FIGS. 16 and 42 , if the value of v is, for example, 10volts, the voltage difference of 20 volts is applied between electrodes285 and 286 between times t1 and t2, times t3 and t4, times t5 and t6,and continuing for the time duration of the waveforms. Waveforms 512 and513 are synchronized and each has a frequency of, for example, 100 Khertz, and a duration of, for example, 0.100 sec. If, for example, theelectrodes 285 and 286 are spaced 8 microns apart, this 20-voltdifferential produces a voltage field of approximately 2.5 million voltsper meter, a level of electrical field intensity that can neutralize(kill) a bacterium cell. The alternating polarities of waveforms 512 and513 serve to make rapid successive applications of field energy to thetargeted pathogen cell between the electrodes. These voltage waveformsare applied each time a total travel time expires for a channel. Theapplied voltage can be adjusted to a value effective to neutralize aspecific pathogen cell. There are many channels in a chamber and therecan be many identified pathogen cells in a channel, thereby theelectrical energy is applied to potentially a substantial number of theidentified pathogen cells.

Continuing reference to FIG. 41C, at step 514, the master controller 434turns the pump 62 off upon expiration of the pump cycle time. This timeis set to be long enough for all of the pathogen cells to flow from themost distant portion of the detection zone to the processing zone. Thatis, longer than the longest total travel time. When the pump 62 has beenturned off, the blood previously in the chambers has been removed andreplaced with a new volume of blood for processing. Following step 514the master controller performs the question step 516 to determine if thetotal processing time has been reached. If the answer to this questionis “NO”, the exit 518 is taken and operations are transferred to step490 (FIG. 41A) to repeat the overall processing operation. If the answerto the step 516 question is “YES”, exit 520 is taken to step 522. Ifthis exit is taken, the total processing time has elapsed. In step 522,the master controller 434 terminates the processing operation and sendsa report thereof to the system controller 14. In step 524 the systemcontroller 14 ends the processing operation and sends a report thereofto its display terminal.

In the above operational description, electrical energy is applied toelectrodes in the processing zone to produce an electric field to killthe detected pathogen cells. But, if the processing zone configurationshown in FIGS. 22 and 23 is implemented, there are no insulating layersbetween the electrodes and the fluid in the channels. In the absence ofthese insulating layers, the electrodes will apply a voltagedifferential directly to the blood thereby creating an electricalcurrent through the blood. This current is selected to be of sufficientamplitude to kill the pathogen cells in the processing zone between theelectrodes.

One embodiment described above has 30 chambers in a single cassette witha sensor, a chamber processor and memory for each chamber. However,embodiments can be implemented having different configurations whichoperate as described above. Further, the embodiments can be scaled bythe number of chambers and/or flow rate through a chamber and/or dataprocessing speed to provide a desired overall flow rate for bloodprocessing. Non-limiting example embodiments are as follows:

-   -   1. 10 chambers each 2.0 cm×2.0 cm, each chamber having a        corresponding light sensor with a single processor and memory        serving all 10 chambers.    -   2. 10 chambers each 4.0 cm×4.0 cm, each chamber having a        corresponding light sensor, processor and memory.    -   3. 30 chambers 2.0 cm×2.0 cm, each chamber having a        corresponding light sensor, and a single processor and memory        serving all 30 chambers.    -   4. 30 chambers divided into a separate 15 chamber Group A and 15        chamber Group B with a sensor for each chamber and a single        processor and single memory for each group.    -   40 chambers each 2.0 cm×2.0 cm and each chamber having a        corresponding light sensor, and a processor and memory for each        set of 10 chambers.    -   6. 100 chambers 2.0 cm×2.0 cm, each chamber having a        corresponding light sensor, processor and memory.    -   7. 100 chambers 2.0 cm×2.0 cm, each chamber having a        corresponding light sensor and having one memory and one        processor for each 10 chambers.

Although several embodiments of the invention have been illustrated inthe accompanying drawings and described in the foregoing DetailedDescription, it will be understood that the invention is not limited tothe embodiments disclosed but is capable of numerous rearrangements,modifications and substitutions without departing from the scope of theinvention.

What is claimed is:
 1. A cassette for use in the treatment of bloodhaving pathogen cells therein, comprising: said cassette having thereinat least one chamber which has an interior space, an input port and anoutput port, said chamber having first and second planar, parallel,opposed walls on opposite sides of said interior space of said chamber,said chamber input and output ports positioned at opposite ends of saidchamber, said cassette having an input port coupled via a firstdistribution line to said chamber input port for transporting said bloodfrom said cassette input port to said chamber, said cassette having anoutput port coupled via a collection line to said cassette output portfor transporting said blood from said chamber to said cassette outputport, said first and second walls transparent to at least a selectedband of light, each of said first and second walls having an interiorwall surface open to the interior of said chamber, said chamber havingan exposure zone which is proximate said chamber input port and aprocessing zone proximate said chamber output port, a plurality ofparallel channels extending from the input port of said chamber to theoutput port of said chamber, said channels passing through said exposurezone and said processing zone, and a plurality of electrodes within saidchamber, said electrodes positioned respectively on side walls of saidchannels within said processing zone.
 2. A cassette as recited in claim1 including a plurality of optical markers in surfaces of said channels,said optical markers at least partially non-transparent to said light.3. A cassette as recited in claim 1 including an electronic driverelectrically coupled to said electrodes.
 4. A cassette as recited inclaim 1 wherein said electrodes are arranged in pairs, each saidelectrode in each said pair of electrodes on opposed sides of acorresponding channel.
 5. A cassette as recited in claim 1 including aplurality of electrical insulators respectively for said electrodes,each said electrical insulator positioned to electrically insulate a oneof said electrodes from the interior of a corresponding one of saidchannels.
 6. A cassette as recited in claim 1 wherein said channels aredefined by a plurality of parallel ridges and by the interior surfacesof said first and second chamber walls.
 7. A cassette as recited inclaim 1 wherein said cassette comprises two planar layers of plasticbonded together and at least one of said layers having said chambers andsaid distribution and collection lines molded therein.
 8. A cassette forthe treatment of blood having pathogen cells therein, comprising: saidcassette having therein at least one chamber which has an interiorspace, an input port and an output port, said chamber having first andsecond planar, parallel, opposed walls on opposite sides of the interiorspace of said chamber, said cassette having an input port coupled via adistribution line to said chamber input port for transporting said bloodfrom said cassette input port to said chamber, said cassette having anoutput port coupled via a second transfer line to said cassette outputport for transporting said blood from said chamber to said cassetteoutput port, said first and second walls transparent to at least aselected band of light, each of said first and second walls each havingan interior wall surface open to the interior of said chamber, saidchamber having an exposure zone which is proximate said chamber inputport and a processing zone proximate said chamber output port, aplurality of parallel channels extending from said chamber input port tosaid chamber outport port, said channels passing through said exposurezone and said processing zone, said channels defined by a plurality ofparallel ridges and by said interior wall surfaces of said first andsecond walls, a plurality of electrically conductive elementscorresponding respectively to said channels and located in saidprocessing zone of said chamber, and an electrical driver circuitmounted to said cassette and electrically coupled to said electricallyconductive elements for selectively applying electrical power to saidblood in said chambers proximate to said electrically conductiveelements.
 9. A cassette as recited in claim 8 wherein the interiorsurfaces of said chamber opposed walls are spaced apart by no more than10 microns.
 10. A cassette as recited in claim 8 wherein said cassettecomprises two planar layers of plastic bonded together and at least oneof said layers having said chambers and said distribution and collectionlines molded therein.
 11. A cassette as recited in claim 8 wherein saidridges comprise spacers between said first and said second walls.
 12. Acassette as recited in claim 8 including a plurality of optical markersin surfaces of said channels, said optical markers at least partiallynon-transparent to said light.
 13. A cassette as recited in claim 8wherein said cassette has a plurality of said chambers therein, saidfirst transfer line comprises an input manifold having the input thereofcoupled to said cassette input port and multiple outputs thereof coupledrespectively to the input ports of said plurality of chambers, and saidsecond transfer line comprises an output manifold having the inputsthereof coupled to respective output ports of said plurality of chambersand the output of said output manifold coupled to said cassette outputport.
 14. A cassette as recited in claim 8 wherein said cassette isfabricated of a plastic which includes an anti-thrombogenic componenttherein.
 15. A cassette for the treatment of blood having pathogen cellstherein, comprising: said cassette having therein at least one chamberhaving an interior space, an input port and an output port, said chamberhaving first and second planar, parallel, opposed walls on oppositesides of the interior space of said chamber, said chamber having arectangular configuration with a width dimension, a length dimension anda thickness dimension, said chamber having an input port positioned onthe width dimension of said chamber, said input port having essentiallya same width as the width dimension of said chamber, said chamber havingan outport port positioned on the width dimension of said chamber and onthe opposite side of said chamber from said chamber input port, saidoutput port having essentially a same width as the width dimension ofsaid chamber, said cassette having an input port coupled via adistribution line to said chamber input port for transporting said bloodfrom said cassette input port to said chamber, said cassette having anoutput port coupled via a collection line to said cassette output portfor transporting said blood from said chamber to said cassette outputport, said first and second opposed walls transparent to at least aselected band of light, each of said first and second walls each havingan interior surface open to the interior of said chamber, said chamberhaving an exposure zone which is proximate said chamber input port and aprocessing zone proximate said chamber output port, a plurality ofparallel channels extending from said chamber input port to said chamberoutport port, said channels passing through said exposure zone and saidprocessing zone, said channels defined by a plurality of parallel ridgesand by said interior surfaces of said first and second walls, and aplurality of electrodes within said chamber, said electrodes positionedrespectively at said channels within said processing zone.
 16. Acassette as recited in claim 15 including a plurality of optical markersin surfaces of said channels, said optical markers at least partiallynon-transparent to said light.
 17. A cassette as recited in claim 15including an electronic driver electrically coupled to said electrodes,said electronic driver mounted to said cassette.
 18. A cassette asrecited in claim 15 wherein said cassette comprises two planar layers ofplastic bonded together and at least one of said layers having saidchambers and said distribution and collection lines molded therein. 19.A cassette as recited in claim 15 wherein said ridges comprise spacersbetween said first and said second walls.
 20. A cassette as recited inclaim 15 wherein said plurality of electrodes are organized in pairs ofelectrodes, each said pair of electrodes corresponding to a one of saidchannels, a first electrode of each said pair of electrodes positionedon one side of a corresponding channel and a second electrode of eachpair of electrodes positioned on the opposite side of the correspondingchannel from the first electrode of the pair of electrodes.